Our purpose is to examine the acute and chronic responses of the pulmonary endothelium of rats and mice to three clinically relevant forms of lung injury: (1) ionizing radiation (delivered as 1, 2, 5, or 10 fractions of 60Co Gamma-rays), (2) monocrotaline ingestion, and (3) bleomycin injections. The acute responses of endothelial cells to injury in situ will be compared with those observed in endothelial monolayers in vitro. Endothelial histology and ultrastructure will be quantitated morphometrically, and will be correlated with four indices of endothelial function: (1) angiotensin converting enzyme (ACE) activity, (2) plasminogen activator (PLA) activity, (3) prostacyclin (PGI2) production, and (4) thromboxane (TXA2) production. ACE, PLA, PGI2 and TXA2 levels in the bronchoalveolar lavage fluid also will be determined. Structural and functional changes in the endothelium will be related to organ function, as demonstrated by pulmonary arterial perfusion scans, and to the anatomic correlates of pulmonary hypertension, i.e. hepato- and cardiomegaly, right heart enlargement, and pulmonary arterial wall thickening. Mechanisms of pulmonary injury at the cellular level will be examined by (1) differential cytology of the lung as determined from histology, ultrastructure, and fluorescence-activated cell sorting of trypsinized lung cell populations at various times after injury, and (2) differential responses of cultured vascular endothelial cells, smooth muscle cells, and fibroblasts in vitro to the three insults. Fluorescein- and peroxidase-labeled ACE antibody binding will be employed to measure the number of endothelial cells in the irradiated lung as a function of time, dose and fractionation. This may clarify the relationship between cell survival and organ function with respect to the pulmonary endothelium. Finally, the ability of the following agents to modify the pathogenesis of endothelial injury in vivo and in vitro will be determined: (1) ACE inhibitors (Captopril, CL242817); (2) PGI2 analogues (CL115347); and (3) antiinflammatories (indomethacin, prenisolone, and penicillamine). These data may identify mechanisms of pulmonary injury, particularly the role of endothelial damage therein, and may reveal steps at which intervention in the pathogenesis of lung injury may be accomplished in a clinically significant manner.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025106-07
Application #
3337962
Study Section
Radiation Study Section (RAD)
Project Start
1979-12-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Molteni, Agostino; Ward, William F; Ts'ao, Chung H et al. (2003) Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin II type I receptor antagonists. Curr Pharm Des 9:751-61
Baybutt, Richard C; Rosales, Cecilia; Brady, Heather et al. (2002) Dietary fish oil protects against lung and liver inflammation and fibrosis in monocrotaline treated rats. Toxicology 175:1-13
Molteni, A; Moulder, J E; Cohen, E F et al. (2000) Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. Int J Radiat Biol 76:523-32
Baybutt, R C; Molteni, A (1999) Dietary beta-carotene protects lung and liver parenchyma of rats treated with monocrotaline. Toxicology 137:69-80
Ts'ao, C; Ward, W F; Tsao, F H et al. (1997) Annexin I in fibrotic rat lung and cultured lung fibroblasts following irradiation. Int J Radiat Biol 72:227-34
Takeoka, M; Ward, W F; Pollack, H et al. (1997) KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells. Am J Physiol 272:L1174-80
Ts'ao, C; Ward, W F; Molteni, A et al. (1997) Annexin I concentration and prostacyclin production in rat lung and alveolar macrophages following irradiation. Prostaglandins Leukot Essent Fatty Acids 56:99-104
Volpert, O V; Ward, W F; Lingen, M W et al. (1996) Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest 98:671-9
Waters, C M; Taylor, J M; Molteni, A et al. (1996) Dose-response effects of radiation on the permeability of endothelial cells in culture. Radiat Res 146:321-8
Cohen, E P; Molteni, A; Hill, P et al. (1996) Captopril preserves function and ultrastructure in experimental radiation nephropathy. Lab Invest 75:349-60

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